Meetings – AMR.Solutions

18-19 Nov 2019 FDA-IDSA-NIH-Pew Workshop: Enhancing Antibacterial Trials in the US

John Rex — Wed, 27 Nov 2019 18:01:00 +0000

Dear All,

Long note alert: Set aside at least 30 minutes for this one … there’s a lot of important material here.

Last week’s workshop entitled “Enhancing the Clinical Trial Enterprise for Antibacterial Drug Development in the United States” was an unusual and unusually instructive meeting. You can go here for the meeting materials but as there are 23 presentations to review, I suggest you use instead the annotated guide to the presentations that you’ll find just below my signature.

Sponsored by FDA, IDSA, NIH (NIAID), and Pew Charitable Trusts, the idea for the workshop arose out of the oft-heard and intertwined critiques that (i) new approvals are for indications that aren’t really the best use of the drug (“We don’t need another drug for cUTI!”), (ii) the approved label does not contain data on how the drug performs vs. really difficult pathogens or in challenging body sites, and (iii) “We don’t have much data on US patients.”

With this as a backdrop, the meeting’s three main goals were to

Review the current state of antibacterial drug development
Obtain stakeholder perspectives on what data would be most informative from development programs for new antibacterial drugs
Evaluate strategies to support generation of the desired data from antibacterial drug development programs

Drawing on the summary deck (link) prepared for the end of the meeting, I offer this 3-part synopsis of the meeting’s very rich discussions:

Part 1: Different stakeholders want different things. This may seem obvious, but we’ve not always (or even often) made sure that we were hearing each other. Because the discussants at the workshop included diverse stakeholders (patients, journals, societies, physicians, charitable funders, government funders, companies), an instructive dialogue arose regarding their different needs.

In particular, there is a real tension between the US legislative requirement that the approved product label contain only very well supported data (the formal description is “Adequate and Well-Controlled”, A&WC) and the value that physicians place on having access to any and all hints about how to treat difficult organisms and unusual sites of infection, even if incomplete. Further, patients may well value outcomes differently — not all adverse events and outcomes are created equal!

In summary form, the different groups want the following:

(ID) physicians want access to all the data, even if incomplete
Payors, P&T committees want ways to judge data quality
Patients want to be heard. Outcomes should include measures of how patients feel!
Companies want validated, acceptable mechanisms for promoting based on data on resistant pathogens and difficult infections
FDA must label products per regulations: “Adequate and well-controlled” data are required

Part 2: There are better ways to share the data we have. So, how do we address these conflicting needs? Intriguingly, four groups of implementable ideas emerged at the workshop for plausible approaches to making better use of the data we have:

First, we must be clear on the limits on data generation
- Because we work so hard to make rare pathogens and rare infections be (and remain!) rare, the choices reduce to either no data or making do with small datasets.
- Even with unlimited time and money, there is no easy fix for this — and while you await those data, what do you tell today’s patient?
- We need to explain the limits to ourselves and our peers – it’s so easy to wish for more data, especially when the constraints on data generation are not obvious.
Second, we must all be clear on FDA’s limits on labeling
- Without rules, we would have arbitrary unpredictable decisions
- “Adequate and well-controlled” (A&WC) is the standard (but see Part 3 for further notes on this)
Third, official society guidelines need to be updated much more often. Because the current update process is so onerous, guidelines can lag practice by years. Alternative approaches (e.g., the rapid guidance updates used in the HCV community, link) should be explored and implemented.
Finally, and recognizing that some very interesting data will never be A&WC, we need to make other data and analyses accessible to the community.
- Publishing data in a major journal about a new drug is of course a good start. Journals need to support this by recognizing that smaller datasets should not be denigrated as “small” when such datasets are the best that can be done.
- In parallel, IDSA (or more broadly, the various professional societies) could publish informed integrated critiques of the available primary and secondary data on new drugs.
  1. Such reviews might be called “Guidance for using Drug X for Difficult Infections and Difficult Pathogens.”
  2. Each by-drug analyses would draw on the FDA label, the FDA medical/statistical reviews, and all other published data to provide a society-led review of all of the available information, both complete and incomplete.
  3. The vision would be for the guidance to be the sort of thing that one peer would tell another about approaches to difficult situations and would be infinitely better than the haphazard data you might find if you went to Medline and searched to find tidbits.
  4. The point here is to recognize that patients present with infections and pathogens that are not (and will never be) discussed in ANY label. When this occurs, it is not an option to say “Sorry, your organism (or infection) is not in the FDA label — please come back when you have a conforming illness.”
  5. Such reviews would / should be appropriate for discussions with payors, discussions with insurers, and (maybe) promotional use. This could be very helpful when, for example, a physician needs to obtain reimbursement approval for use of an agent for an unusual situation.

Part 3: We can make better use of the data we do routinely generate. The ideas here require a bit more work but also seem within reach:

First, we can reduce our angst about the need for data from patients in the United States. We would still like at least some such data, but FDA has done a deep review of this topic (see this talk) and it turns out that the studies generalize pretty well across national lines.
Second, we must all be clear on the power of the standard indication (e.g., cUTI) based on a modern non-inferiority (NI) trial
- Modern NI studies are powerful tools that readily detect inferior agents (go here for more details)
- NI trials provide clear safety and efficacy comparisons
- NI trials facilitate initial approval and thus provide a basis for additional indications
Third, we can probably do more with the data we do have, up to and possibly including the scope of the data we can put in labeling
- Please look closely at the 4 statistical talks in the last section of the meeting agenda!
- As one path, we need to learn to apply statistical methods of borrowing data (information) across sites of infection.
- As another element, we also need to think about the words Adequate and Well in the idea of A&WC. The same thresholds for validity do not apply to all settings — we must make accommodations for rarity.
- Finally, don’t forget PROs (Patient-Reported Outcomes) and other patient-oriented measures! These can be incorporated into endpoints by use of advanced statistical methods thereby adding some additional information to otherwise dichotomous success/fail endpoints.
Finally, we can run trials more efficiently
- They are not a panacea, but platform trials show real potential to reduce cost and speed data generation. This seems particularly true after initial approval is achieved: studies in pediatrics and rare infections would seem a particularly good fit
- And trial process improvements are also possible. As one example, obtaining consent in high-risk patients before they develop an infection seems workable!

All in all, this was an excellent conversation that leaves us with some clear actions. Some of the actions can be taken promptly and would have immediate benefit to the community. In particular, I am very excited about the ideas of (i) more frequent guideline updates and (ii) society-led “Guidance for using Drug X for Difficult Infections and Difficult Pathogens.” Others ideas (e.g., ordinal endpoints and data borrowing) will require more conversation be seem well positioned for use.

Nothing is set in stone, but I am hopeful that we’ll have the next iteration of this conversation at a follow-up workshop in the not too far distant future.

Many thanks to FDA, IDSA, Pew Trusts, and NIAID for organizing this workshop! All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://13.43.35.2/blog/

Outline of presentations at the 18-19 Nov 2019 FDA-IDSA-NIH-Pew Public Workshop.
The home page for the meeting is here and the links below are drawn from that web page. The presentation order is slightly re-arranged from the actual meeting so that talks are grouped logically for this summary. Panel discussions did not include slides and hence are not captured here.

Introductory Comments, Meeting Summary, and related notes
- Welcome and Panel Introduction (John Farley, FDA; link)
- Meeting Summary (John Rex, F2G; link)
- Agenda (link)
- Speakers and Panelists (link)

Current State of Play
- Overview of Antibacterial Trials (Sumathi Nambiar, FDA; link)
  - Why are we here today? Lessons learned and Rules of the Road for FDA
- Geographic Shifts in Antibacterial Drug Trial Enrollment: Implications for Generalizability (Stephen Bart, FDA; link):
  - US data are important, but demographic, clinical, and microbiological similarities across regions lessen generalizability concerns for antibacterial drug trials
- Current Constraints in Antibacterial Drug Development: Clinician’s Perspective (Helen Boucher, Tufts Medical Center; link)
  - The crisis of AMR is here NOW! ID physicians need new drugs and know how to work with incomplete data
- Role of Antibiotic Stewardship Programs in Utilization of Antibacterial Drugs (Sara Cosgrove, Johns Hopkins University; link)
  - A review of real-world challenges with positioning new antibacterials in hospitalized patients
- Patient Perspective on Clinical Trial Participation (Amy Leitman, NTM Info and Research; link)
  - Patients both have things to tell us (please incorporate patient-reported outcomes and wish for better messaging from their caregivers
- Review of Antibiotics in Clinical Development Pipeline (Wes Kim, Pew Charitable Trusts; link)
  - Most compounds currently in clinical development are based on known classes. Of the 13 candidates in Phase III development, three are based on novel classes (but one has now been discontinued) and (ii) only six have expected activity against a CDC ‘Urgent’ threat.
- Current Federal Efforts to Support Antibacterial Drug Development (Dennis Dixon, NIAID, link; Erin Duffy, CARB-X, link ; Mark Albrecht, BARDA; link)
  - Collectively, BARDA, NIAID, and CARB-X have deployed an impressive array of resources
- Economic Challenges and Considerations in Antibacterial Drug Development (Kevin Outterson, CARB-X; link)
  - The “Check Engine” light is flashing on the AMR enterprise — all our hard work is at risk unless we act now

Realistic Options for Enhancing the Antibacterial Trial Enterprise
- What Do We Need, What Should We Be Doing, Who Should be Doing It? (John Rex, F2G; link)
  - It’s time for Antibiotic R&D 3.0: Let’s all row the boat together … and in the same direction
- Impact of Publications on Clinical Care and Research of Antibacterial Drugs (Lindsey Baden, Harvard University; link)
  - Publishers face competing demands from different stakeholders: Data mean different things depending on your point of view. Publishers should facilitate, air, and provoke discussion from all perspectives
- Updating Professional Society Guidelines for Bacterial Infections (Cynthia Sears, Johns Hopkins University; link)
  - Guidelines and Guidance: Upholding methodological rigor while meeting a reduced development timeframe
- Pitfalls and Progress in Getting Clinicians the Trials They Need (Vance Fowler, Duke University; link)
  - Registrational Trials are necessary but not sufficient, Strategy Trials will give clinicians what they want, and
    Clinical Networks can improve US participation in both types of studies
- Enhancing Clinical Trial Enrollment Strategies (Pamela Tenaerts, CTTI; link)
  - Process improvement is possible in HABP-VABP trials! With some limitations, CTTI has validated a way to obtain consent from high-risk patients in advance of the onset of an infection.
- International Clinical Trial Networks (Chibuzor Uchea, Wellcome Trust; link)
  - International Trial Networks and Continuous Master Protocols are mutually supportive ways to enhance efficient trial implementation

Innovative Statistical Approaches
- FDA Statistical Perspective (Dan Rubin, FDA; link)
  - Areas for improvement include (i) Ordinal endpoints (e.g., Death < Survival with major morbidity < Survival without major morbidity), (ii) Borrowing of data across body sites, and (iii) Techniques for incorporation of resistant pathogen data into trial programs
- Statistical Approaches for Antibiotic Trials (Roger Lewis, Berry Consultants; link)
  - A multi-infection-site, multidrug, platform trial could efficiently address non-inferiority and superiority evaluations of new agents targeting highly resistant pathogens
- Radical Pragmatism: DOOR and SMART COMPASS for the Evaluation of Antibiotics (Scott Evans, George Washington University; link)
  - Simple Success/Fail endpoints lose valuable information that matters to patients and doctors. We can do better
- An Alternative Design for Trials of Patients with Rare Pathogens: Conducting Trials with Difficult to Find Cases (Aaron Dane, DaneStat Consulting Limited; link)
  - Small studies (40-50/arm) efficiently detect inferior and superior drugs. Recognizing this enables better use of limited data.

Upcoming meetings of interest to the AMR community:

26 Nov 2019 (webinar, 9:30-11:00 CET): REVIVE webinar entitled “Innovation in point-of-care diagnostics for sepsis and bloodstream infections.” Go here to register.
28-29 Nov 2019 (Birmingham, UK): BSAC workshop entitled “ARM (Antibiotic Resistance & Mechanisms)”. This meeting is a research forum for UK-based researchers at all levels, including PhD students and technicians. Go here for details.
5 Dec 2019 (Monthey, Switzerland): The BioArk technology park is holding a one-day workshop on AMR. Entitled “The Ark Life Sciences Series #1”, you can get more details here.
16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
16 Jan 2020 (Washington, DC): Duke-Margolis meeting entitled (approximately) “improving Payment Policies for Antibiotics.” This meeting will run 10:30am – 4:30pm ET. Go here to register.
20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): Gordon Research Conference (GRC) on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
12-13 Mar 2020 (Basel): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Details are here, poster deadline is 12 Dec 2019.
16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details.
18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
27-28 Jun 2020 (Bryant University, Rhode Island): Drug Resistance Gordon Research Seminar entitled “Mechanisms and Approaches to Overcoming Drug Resistance in Cancer, Infectious Disease and Agriculture” for graduate students and postdoctoral scientists. Go here for details … this immediately precedes the GRC listed just next
28 Jun-3 Jul 2020 (Bryant University, Rhode Island): Gordon Research Conference (GRC) entitled “Strategies to Disrupt Drug Resistance in Infectious Disease, Cancer and Agriculture.” Go here for details.
1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
22-25 Sep 2020 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
17-25 Oct 2020 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics and resistance. The course is very intense, very detailed, and gets rave reviews. The date is set for 2020 and the program will ultimately appear here. Registration is limited to 40 students and opens 15 Mar 2020.
10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

Save the date: 18-19 Nov 2019 FDA-IDSA-NIAID-Pew-sponsored workshop: “How can we improve antibacterial development?”

John Rex — Fri, 04 Oct 2019 06:03:18 +0000

Dear All,

Please mark your calendar now to be in the Washington, DC area on 18-19 Nov 2019 for a 2-day workshop at FDA’s White Oak Campus focused on enhancing the clinical trial enterprise for antibacterial drug development.

Jointly co-sponsored by FDA, IDSA, NIAID, and Pew Trusts, this meeting will have a particular focus on (a) multi-stakeholder challenges and (b) changes that could be made in the United States to enhance the development of antibacterial drugs.

The program is expected to cover these topics:

What data do various stakeholders (clinicians, patients, developers, FDA) need?
Where there are gaps in data, what data are possible?
How can we use innovative trial design elements (e.g., novel statistical methods) to generate better data?
Can we facilitate trial conduct via such tools as trial networks?
What is the role of scientific journals in spreading the word on what is known, not known, and possible to know?
Likewise, what is the role of scientific societies educating the community? Can guideline updates be more frequent and timely?

I think this will be an important meeting and I would encourage the developer community to make every effort to attend either in person or by webcast. The general webpage for the meeting is here and the registration page is here. The meeting to runs 8.30a-5.30p on Day 1 and then 8.30a-1.00p on Day 2.

All best wishes, –jr

Upcoming meetings of interest to the AMR community:

8 Oct 2019 (London): Launch of “Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done?”, a follow-up to the UK AMR Review‘s report and recommendations. Go here to register.
10 Oct 2019 (online): Deadline for feedback to the Global AMR R&D Hub on their draft Collaboration Framework. Go here to tell them what you think!
11 Oct 2019 (online): Deadline for Novo REPAIR’s 2019 US-Canada investment round. Go here for details — you need to dig all the way to the bottom of the web page.
16 Oct 2019 (FDA, White Oak): Advisory Committee for NDA 209445, cefiderocol lyophilized powder for intravenous administration, submitted by Shionogi Inc., for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis due to gram-negative bacteria in patients with limited or no alternative treatment options. Go here for details.
19-27 Oct 2019 (Annecy, France): International Course on Antibiotics and Resistance (ICARe) – A soup-to-nuts intensive residential training program on all things AMR, especially R&D for new antibiotics. See this link for details.
4 Nov 2019 (FDA, White Oak): Public hearing on FDA’s proposed rules for “Use of Fecal Microbiota for Transplantation to Treat Clostridioides (Clostridium) difficile.” Go here for the online FR notice and here for the .pdf version.
7 Nov 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Converting Gram-positive-only compounds into broad-spectrum antibiotics.” Go here to register.
14-15 Nov 2019 (Hamilton, Ontario): “Fueling the Fight Against Antimicrobial Resistance”, a 2-day Gairdner Foundation-sponsored symposium in collaboration with the Michael G. DeGroote Institute for Infectious Disease Research and the David Braley Centre for Antibiotic Discovery at McMaster University. Go here for details.
[NEW] 18-19 Nov 2019 (FDA, White Oak Campus): FDA-IDSA-NIAID-Pew-sponsored workshop: “Enhancing the Clinical Trial Enterprise for Antibacterial Drug Development in the United States.” Mark your calendar now, details to follow.
19 Nov 2019 (London): BSAC seminar entitled “Into clinical practice: Meeting the challenges of Gram-negative infection management”. A one-day conference on treatments for Gram-negative infections. Go here for details.
28-29 Nov 2019 (Birmingham, UK): BSAC workshop entitled “ARM (Antibiotic Resistance & Mechanisms)”. This meeting is a research forum for UK-based researchers at all levels, including PhD students and technicians. Go here for details.
16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
21 Jan 2020 (London): BSAC’s 2nd Antimicrobial Chemotherapy Conference – An ABC for everyone involved in developing new antimicrobials. Go here for details.
20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): GRC on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
12-13 Mar 2020 (Basel, I’m told): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Final location is TBD, details will appear here, and you should mark your calendar now.
16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details.
18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)
1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.

FDA workshop: Insights on inhaled antifungals and antibacterials

John Rex — Sun, 18 Oct 2020 17:22:34 +0000

Dear All (wonkish alert … coffee up!),

FDA held a workshop on 25 Sep 2020 on development of inhaled antifungal (AF) therapies with a focus on (i) therapies for allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), (ii) prophylaxis in lung transplantation, and (iii) adjunct therapy in invasive fungal lung infections (link to FDA webpage with meeting materials).

Aside #1: Note that the focus of this workshop was deliberately NOT on cystic fibrosis (CF): If you are interested in developing drugs for CF, please see this excellent slide deck that Bruce Montgomery shared with me on this topic. You might also want to review the funding opportunities provided by the Cystic Fibrosis Foundation.

Aside #2: A manuscript has been published based on this workshop and is a good summary of the discussion: Jjingo CJ, et al. Food and Drug Administration Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development. Clin Infect Dis. 2024 Jun 14;78(6):1564-1570. https://doi.org/10.1093/cid/ciad607. PMID: 37802928.

To fully appreciate the insights from the 25 Sep workshop, it is necessary to also be aware of prior material on development of inhaled therapies for bacterial and mycobacterial lung diseases:

6 Jun 2017: At the ISAM (International Society for Aerosols in Medicine) congress, FDA’s Sumati Nambiar gave a talk on inhaled antibacterial development (link to newsletter; it links to the ISAM talk as well as a talk on development for HABP-VABP at ASM Microbe).
16 Nov 2017 FDA Advisory Committee on Bayer’s inhaled ciprofloxacin for non-CF bronchiectasis (NCFB, link to meeting materials).
- In brief: Mixed results from a pair of big Phase 3 trials (one trial had a significant finding, the other did not), favorable trends were of small magnitude, and patient heterogeneity seemed an issue.
11 Jan 2018 FDA Advisory Committee on Aradigm’s inhaled ciprofloxacin for NCFB (link to meeting materials).
- In brief: Similar to the Bayer data, mixed results from a pair of big Phase 3 trials with similar data issues.
7 Aug 2018 FDA Advisory Committee on Insmed’s inhaled amikacin for non-tuberculous mycobacterial lung disease (NTM, link to meeting materials).
- In brief: Data from two studies show reduced organism load in sputum but (i) there was no clear clinical benefit based on changes in a 6-minute walk test (one trial had a favorable trend, the other did not) and (ii) the inhaled therapy had a notably higher rate of discontinuation for adverse events such as cough or bronchospasm.
8 Apr 2019 FDA Workshop on therapies for NTM lung disease (link to newsletter providing extended notes on that workshop).
- In brief: (i) Clearing NTM from the lungs is hard, (ii) conversion to a negative culture has a weak link to symptoms, and (iii) seeing a clear effect of therapy is confounded by issues such as structural lung disease, baseline heterogeneity, and AEs due to inhaled therapies.

Putting everything together, the key message is that inhaled therapies for pulmonary infections are surprisingly hard to develop. Let’s take the discussion in pieces based on this outline:

Drug delivery is hard: Inhaled therapies for pulmonary infections sound like they would be a great idea but uniform delivery to the lung is hard (and may not even be possible).
For the non-invasive syndromes, associated symptoms have many causes as well as a range of severity and durations: For illnesses characterized by exacerbations (NCFB, ABPA, SAFS), the seemingly obvious endpoints of time-to-exacerbation and exacerbation frequency give inconsistent results. For all syndromes, patient heterogeneity creates noise, underlying structural lung disease is not going to be corrected, and other events (e.g., intercurrent viral infections) will further add noise.
For the non-invasive syndromes, microbiologic endpoints are not the answer: Reduction in organism load does not equate to clinical benefit.
For the non-invasive syndromes, would a PRO (or two) help the field? What matters is how the patient feels — can we develop suitable patient-reported outcome (PRO) tools?
Prevention of invasive syndromes in lung transplant is intriguing but prophylaxis is now standard and hence new agents would have to be studied in a non-inferiority design trial.
Impact of an adjunct inhaled AF in treatment of active infection will be hard to show because concomitant systemic therapy is likely needed. Hence a new agent would need to show superiority over the outcome with well-dosed systemic therapy.

—
Drug delivery is hard: Although Inhaled therapies for pulmonary infections sound like they would be a great idea, this image from the talk by Dr. Bensman from FDA really puts things into perspective (link to directly download his talk; MDI = Multi-Dose Inhaler). Note at left that even a healthy person can struggle to get consistent distribution — training helps as does as a breath-actuated device but distribution still imperfect. Then at right we have the real problem: airflow in abnormal lungs is (doh!) abnormal. I think it is obvious that areas that really need the drug may well not get it.

—
For the non-invasive syndromes, associated symptoms have many causes as well as a range of severity and durations: For illnesses characterized by pulmonary symptom exacerbations (NCFB, ABPA, SAFS), the seemingly obvious endpoints of time-to-exacerbation and exacerbation frequency have given inconsistent results across trials to date. You can see this for both bacterial infections (links above) as well as for the fungal syndromes (direct link to the talk at the workshop by Denning; it has good listings of prior studies).

A further subtlety that comes out when you read the comments in the FDA briefing books for the inhaled ciprofloxacin studies is that frequency of exacerbation gets confused by the fact that the duration of an exacerbation subtracts from the total at-risk period for an exacerbation … so, there is the counterintuitive possibility that having a single exacerbation will actually reduce apparent exacerbation frequency over any given period of time! For more on this point, go to page 38 in FDA’s BB for the Bayer product and to page 31 in FDA’s BB for the Aradigm product.

Finally, my reading is that all the studies have struggled with signal-to-noise ratio. Patient heterogeneity definitely creates noise, underlying structural lung disease is not going to be corrected by these therapies, and other events (e.g., intercurrent viral infections) will occur. To my eye, this means therapies that produce a real but only modest benefit will struggle to show impact.

As a demonstration of this, the paper Kollef et al. entitled “A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial” (Chest. 2017 Jun;151:1239-1246. doi: 10.1016/j.chest.2016.11.026) showed that adjunct inhaled amikacin + fosfomycin reduced organism burden but had no discernable effect on clinical outcome in VAP.

As a counterpoint, the use of organism load as a surrogate marker led to an accelerated approval by FDA for Insmed’s inhaled amikacin for NTM (refractory disease only) that seems likely to have been a one-off that was possible only because there were no approved therapies for that disease. Insmed’s FDA approval (link to press release) requires that they conduct a further randomized trial to demonstrate the clinical benefit. CHMP issued a positive opinion in July 2020 for European approval (link to PR) but we’ll have to await the actual approval to see if it is (as one would guess) conditional on completing a trial similar to that required by FDA.

—
For the non-invasive syndromes, would a PRO (or two) help the field? What matters is how the patient feels — can we develop suitable patient-reported outcome (PRO) tools? This certainly seems like a useful strategy, but it is also one that has some complexity. At a conceptual level, the idea of PRO sounds really good … ask the patient how s/he feels over time and use that as the endpoint.

The tricky thing with PROs, however, is that they typically have 5-10 elements (e.g., pain, ability to do activities of daily living, cough) with each element scored on an ordinal scale using patient scores such as No Symptoms/Limitations – Mild – Moderate – Severe – Disabling. A five-level score like this can be coded as 1-5 (1 = best, 5 = worst).

So, let’s imagine a 5-element PRO and Patient A with a baseline score of 22333 that becomes 11333 after a few weeks. Looks good: the first two scores are better, the others are the same. How about Patient B: 44333 and then 33332 after a few weeks. Again, better … but now who improved the most? Are some elements more important than others? After a while, the mind boggles and you start to really wish for something as simple as “Cured” vs. “Not Cured.”

This is clearly an area where further research needs to be done!

—
Prevention of invasive syndromes in lung transplant is intriguing but the talk by Dr. Husain (direct link) made it clear that prophylaxis is now standard in lung transplant. Hence new agents would have to be studied in a non-inferiority (NI) design trial (link to recent newsletter on the importance of NI designs). I’ve not dug deeply into the literature, but the effect sizes don’t look very large (slides 7-8 from the talk by Dr. Marr, link). This, in turn, could mean that a very large trial is required to show utility of a new agent.

—
Impact of an adjunct inhaled AF in treatment of active infection will be hard to show because systemic therapy is likely needed. Hence a new agent would need to show superiority over the outcome with well-dosed systemic therapy. This is a variation on the problem that we have with non-traditional therapies in general (link to newsletter). Showing incremental superiority over an effective therapy is hard because (i) we go to great lengths in trials to avoid giving ineffective therapy in the control arm and (ii) events unrelated to AF therapy (e.g., progression of malignancy) confound data interpretation.

—
Ok, so we’re now at the end of our tour. It’s been very interesting to review these materials and contemplate at length why such an attractive idea is so hard to pursue in practice. It’s clear that there are patients with serious illness who are not well served by available therapies, but it is equally clear that a lot of work is needed before we’ll have a practical pathway that leads to approval of novel inhaled antifungal and antibacterial products. My thanks to FDA for convening this excellent (albeit sobering) discussion.

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Current funding opportunities (most current list is here):

Novo REPAIR Impact Fund closed its most recent round on 31 Jul 2020. Go here for current details.
2020 funding rounds for CARB-X have not been announced.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes funders and projects by geography, stage, and more.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
[NEW] ARLG (Antibiotic Resistance Leadership Group, link) is currently open for applications for its 2-year ARLG Fellowship program. The application deadline is 1 Dec 2020; full details are here.
Finally, you might also be interested in the most current lists of R&D incentives (link) and priority pathogens (link)

Upcoming meetings of interest to the AMR community (most current list is here):

In case you missed it, the 24 Sep 2020 Bootcamp #1 (“Moving from preclinical to clinical-stage: Challenges & opportunities”) is now available for replay: Get it here. The video for the 8 Oct 2020 Bootcamp #2 (“Exploring safety issues in antimicrobial drug development”) will follow shortly — check back at the current meetings webpage (link) to find it.
21 Oct 2020 (online, 9:00-10:30 CEST): GARDP-sponsored webinar entitled “Building better breakpoints: data and methods needed to determine breakpoints for new agents” moderated by Gunnar Kahlmeter. Go here to register.
21-25 Oct 2020 (online meeting): IDWeek 2020. Go here for details.
26-29 Oct 2020 (online meeting): Annual ESPID meeting (European Society for Pediatric ID, #38)
27 Oct 2020 (online, 9a-5p EST): FDA Workshop entitled “Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.” Go here to register.
27 Oct 2020 (online meeting): BARDA Industry Day, a discussion of U.S. Government medical countermeasure priorities. Mark your calendar now and watch this website for details.
29 Oct 2020 (online, 4-6pm Paris): 5th anniversary ICARe (Interdisciplinary Course on Antibiotics and Resistance) webinar. This fabulous week-long residential course can’t be held this year but Patrice Courvalin is organizing a 2-h anniversary webinar both for former attendees and anybody else who is interested. Speakers will include Patrice as well as Helen Boucher, Gerry Wright, Erin Duffy, and me. Go here to register.
5 Nov 2020 (online, 9-10.30am EST) webinar entitled “Aiming in the dark: what happens when disease spreads without diagnosis”, the third webinar in a 4-part series sponsored by Wellcome Trust entitled “AMR in the Light of COVID-19 Webinar Series; From hypothetical to reality: How COVID-19 foretells a world without antibiotics.” Go here to register.
16 Nov 2020 (online, 9.30a-4.00p EST): FDA workshop entitled “Potential Approach for Ranking of Antimicrobial Drugs According to Their Importance in Human Medicine: A Risk Management Tool for Antimicrobial New Animal Drugs.” Go here for the FR notice and here for extended details, including registration.
17 Nov 2020 (online, 17:00-18:30 CET): GARDP-sponsored webinar entitled “Discovery of new antibacterials using artificial intelligence (computational chemoinformatics)” moderated by Laura Piddock. Go here to register.
18-24 Nov 2020 (everywhere): World Antimicrobial Awareness Week. For resources, go here for WHO’s home page for the week. The focus will be on two messages: “Antimicrobials: handle with care” and “United to preserve antimicrobials.”
19 Nov 2020 (online, 9-10.30am EST) webinar chaired by Jeremy Knox entitled “Responding to difficult-to-treat infections: Role and responsibilities of governments, researchers, clinicians, industry and patients”, the final webinar in a 4-part series sponsored by Wellcome Trust entitled “AMR in the Light of COVID-19 Webinar Series; From hypothetical to reality: How COVID-19 foretells a world without antibiotics.” Go here to register.
26-28 Jan 2021 (online, runs ~7.30a-5.00p Central each day): 4th Annual Texas Medical Center Antimicrobial Resistance and Stewardship Conference. Sponsored by McGovern Medical School, ARLG, and the Gulf Coast Consortia, the agenda includes both poster sessions and keynotes. The call for abstracts closes 18 Dec 2020. Go here for more details.
9-12 Jul 2021 (Vienna): Annual ECCMID meeting (#31)
18-21 May 2021 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
20-24 June 2021 (Toronto): International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-12). Go here for details.
3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.
27 Jun-2 Jul 2021 (Ventura, CA): Gordon Research Conference entitled “Antimicrobial Peptides”. Go here for details, go here for the linked 26-27 Jun Gordon Research Seminar that precedes it.
5-21 Aug 2021 (Marine Biology Laboratory, Woods Hole, MA): Residential course entitled “Molecular Mycology: Current Approaches to Fungal Pathogenesis.” This 2-week intensive training program has run annually for many years and gets outstanding reviews. Go here for details.
8-11 Oct 2021 (Aberdeen, Scotland): 10th Trends in Medical Mycology. Go here for details.
16-24 Oct 2021 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. The course is very intense, very detailed, and gets rave reviews. Registration is here and is limited to 40 students.
6-11 Mar 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.

FDA-NIAID-CDC: Developing drugs for gonorrhea, 23 Apr 21 workshop

John Rex — Tue, 13 Apr 2021 20:30:58 +0000

Dear All,

FDA, NIAID and CDC have announced a public workshop on development considerations of antimicrobial drugs for the treatment of gonorrhea. The workshop will cover both nonclinical (preclinical) and clinical trial design considerations:

Animal models
Clinical pharmacology considerations
Trial design considerations for gonorrhea, such as enrollment strategies, choice of comparators and site of infection.

The workshop is being held virtually on 23 Apr 2021 from 9a-5p EST. The workshop’s webpage is here and provides details on how to attend, how to make an oral presentation, etc. Registration is here.

This is a timely meeting given that emergence of resistance has created a powerful global need for new products for gonorrhea. That noted, developing for this infection has some unusual aspects that will make this a very informative workshop: in particular, the human specificity of N. gonorrhoeae has made animal models (and hence, PK-PD work to guide dose selection) difficult. It will be interesting to learn the updates on work (e.g., transgenic models) intended to help with this issue.

All best wishes, –jr

Current funding opportunities (most current list is here):

Novo REPAIR Impact Fund will open its next global call on 1 April 2021. Go here for current details.
NIAID’s 2021 Broad Agency Announcement for product development is entitled “Development of Medical Countermeasures for Biothreat Agents, Antimicrobial-Resistant Infections an Emerging Infectious Diseases” and is now live with a 24 May 2021 deadline. Research areas include Vaccines, Therapeutics, and Sequencing-Based Diagnostics.
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

20-22 April 2021 (online, 1-5p CET): JPIAMR-sponsored workshop entitled “Feeding the Antimicrobial Therapeutics Pipeline.” JPIAMR, the collaborative global effort of 28 countries (much of the EU and also Argentina, Canada, Egypt, Israel, Japan, Korea, South Africa, and Turkey), is organizing a mixture of keynote talks, abstract presentations, and discussion panels designed to encourage collaborative antibiotic R&D. Go here for more details and registration. Abstract deadline is March 17^th 2021; no previous JPIAMR funding required.
21-22 April 2021 (online, 9a-5p UK): 2021 BioInfect Conference sponsored by BioNow, the Northern England business support group. Go here to register.
23 Apr 2021 (online, 9a-5p EST): FDA-NIAID-CDC workshop entitled “Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.” The workshop’s webpage is here; go here to register.
29 April 2021 (online, 5-6.30p CEST): GARDP-sponsored webinar entitled “AMR R&D efforts in the CMC and formulation arena: Do it right the first time!” Go here to register.
10-12 May 2021 (virtual): UK-focused Virtual AMR Innovation Mission sponsored by Innovate UK in collaboration with AMR Insights and Oxford innovation. This free 3-day virtual event seeks to connect AMR-focused start-ups, SMEs and Multinationals, Academia, Research Institutes, Regional Development Companies and other interested stakeholders in the UK, Europe and other parts of the world. It will be followed (COVID-willing!) by a face-to-face mission scheduled for 11-15 Oct 2021. Go here for more details.
[NEW] 13 May 2021 (virtual, 9.30-11.00a EST): CDC-sponsored webinar entitled “AMR in a Changed World: Building Resilient Systems for Today and Tomorrow.” Moderated by CDC’s Michael Craig, an international panel will discuss “where we go from here to address AMR after the COVID-19 pandemic.” Go here to register.
18-21 May 2021 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
24-29 May 2021 (online and in Geneva): ESPID 2021, the 39th Annual Meeting of the European Society for Paediatric Infectious Diseases. Save-the-date announcement is here, details to follow.
20-24 June 2021 (Toronto): International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-12). Go here for details.
20-24 Jun 2021 (virtual, various times): World Microbe Forum sponsored by the American Society for Microbiology (ASM) and the Federation of European Microbiological Societies (FEMS). Go here for more details and to register.
27 Jun-2 Jul 2021 (Ventura, CA): Gordon Research Conference entitled “Antimicrobial Peptides”. Go here for details, go here for the linked 26-27 Jun Gordon Research Seminar that precedes it.
9-12 Jul 2021 (virtual): Annual ECCMID meeting (#31)
[NEW] 26 Jul-30 Jul 2021 (online): Small World Initiative Instructor Training Workshop – training for undergraduate professors in the wet lab techniques, parallel curricula, & pedagogical instruction to engage students in the hunt to find new antibiotic-producing soil microbes. Go here to register.
14-29 Aug 2021 (Marine Biology Laboratory, Woods Hole, MA): Residential course entitled “Molecular Mycology: Current Approaches to Fungal Pathogenesis.” This 2-week intensive training program has run annually for many years and gets outstanding reviews. Go here for details.
8-11 Oct 2021 (Aberdeen, Scotland): 10th Trends in Medical Mycology. Go here for details.
11-15 Oct 2021 (physical, somewhere in the UK): UK-focused Innovation Mission sponsored by Innovate UK in collaboration with AMR Insights and Oxford innovation. This free event seeks to connect AMR-focused start-ups, SMEs and Multinationals, Academia, Research Institutes, Regional Development Companies and other interested stakeholders in the UK, Europe and other parts of the world. Go here for more details.
16-24 Oct 2021 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. The course is very intense, very detailed, and gets rave reviews. Registration is here and is limited to 40 students. Bonus feature: For obvious reasons, the course didn’t happen in 2020! But as a celebration of the course’s 5th year, a webinar version was held on 29 Oct 2020: go here to stream it.
25-28 Oct 2021 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
6-11 Mar 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.

JPIAMR Diagnostics Call / James Bond’s occupational exposures

John Rex — Wed, 08 Feb 2023 02:28:29 +0000

Dear All, A short one today! Please peruse both the funding opportunities and upcoming meetings just below my signature. Of special note:

Building on the call in the recent biodefense-focused BAA from NIAID for diagnostic applications, JPIAMR is also looking for diagnostic applications (7 Mar deadline).
Very interesting 2 Mar 2023 Duke-Margolis webinar entitled “Data Capture to Measure, Track, and Improve Antibiotic Use.”
Several webinars from WHO with a strong focus on implementation of National Action Plans (NAPs) for AMR

Also, I cannot resist the urge to share No time to die: An in-depth analysis of James Bond’s exposure to infectious agents by Graumans et al. in Travel Med Inf Dis 2021. I only recently discovered this gem in which the authors review (among other things) The Man with the Golden Gut, A Flu to a Kill, and The Fly Who Loved Me. YOW! It’s clear that the authors had a good time researching and writing this fun paper!

And if you are in the mood for more pop culture antibiotic tie-ins, I continuously update the online copy of the newsletter entitled “Movies to Discover Antibiotics By!” … check it out along with the ongoing YouTube series of the same name!

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Current funding opportunities (most current list is here)

[NEW] JPIAMR call for projects on AMR Diagnostics and Surveillance. Under the collaborative umbrella of ERA-NET, this JPIAMR-ACTION project seeks development of innovative strategies, tools, technologies, and methods for diagnostics and surveillance of antimicrobial resistance. The project involves 23 funders from 19 countries and the total estimated call budget is about 19,1 million Euro. Go here for the full webpage on the call. Pre-proposals are due by 7 Mar 2023.
NIAID BAA with a biodefense focus: Vaccines, Therapeutics, and Diagnostics are all in scope. See this newsletter for details; various due dates through 11 April 2023.
Current funding rounds from CARB-X are as described in this newsletter!
The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
BARDA’s long-running BAA-18-100-SOL-00003 offers support for both antibacterial and antifungal agents. This BAA has offered 4 deadlines/year since 2018 … check the most current amendment for details.
INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

[NEW] 14 Feb 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO People-centred framework on addressing AMR” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
[NEW] 2 Mar 2023 (virtual, 1.00-2.35p ET): Webinar from Duke-Margolis entitled “Data Capture to Measure, Track, and Improve Antibiotic Use.” The panel discussion at this webinar will seek to inform possible policy approaches that could be used as part of incentives for novel antibiotics. Timely! The meeting’s website is here; go here to register.
[NEW] 16 Mar 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO AMR Costing & budgeting tool: A review and country experiences” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
16-17 Mar 2023 (timings suggest hybrid EU-US): 7th AMR Conference, hosted by the BEAM Alliance with many co-sponsors. This has historically been a very good networking event. Go here for details.
[NEW] 23-24 March 2023 (virtual, 10a-4p ET): 23^rd Meeting of the Presidential Advisory Council on Combating Antibiotic Resistance (PACCARB). The PACCARB will vote on the report from the Pandemic Preparedness Working Group (PPWG) on how to strengthen defenses against AMR pathogens in the face of a potential future, large-scale disease event. Go here for details and to register.
14 Apr 2023 (Copenhagen, Denmark; 3-6.30p CEST): ECCMID and the Global Leaders Group on AMR will jointly sponsor a symposium entitled “Forging partnerships between science and policy in Antimicrobial Resistance (AMR).” Go here to register.
15-18 Apr 2023 (Copenhagen, Denmark): 33rd ECCMID. Go here for details and to register.
[NEW] 26 Apr 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO Human health AMR research agenda” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
8-12 May 2023 (Lisbon, Portugal): 41st Annual Meeting of the European Society for Paediatric Infectious Diseases. Go here for details.
[UPDATED DATES] 7-15 Oct 2023 (residential, Annecy, France): ICARe, the Interdisciplinary Course on Antibiotics and Resistance. Now in its 7th year, this course is a deep-dive into the world of antibiotic development. Intense, rigorous, and HIGHLY recommended. Seats are always limited … apply sooner rather than later! Go here for details.
20-23 Oct 2023 (Athens, Greece): 11th TIMM (Trends in Medical Mycology). Go here for details.

Public meeting on the LPAD Pathway: Post-meeting thoughts (wonkish)

John Rex — Mon, 22 Jul 2019 11:12:31 +0000

Long and wonkish note alert — please refresh your coffee before you start reading!

Dear All:

I was able to attend and speak at the 12 July 2019 Public Meeting organized by FDA on the LPAD (Limited Population Antibacterial and Antifungal Drug) pathway. The current draft guidance is here and the meeting agenda is found here. The meeting was captured for streaming replay and the video, all the slides, and a transcript will be available here in a few weeks. Post-newsletter addendum: The LPAD guidance is final as of August 2020. The essence is unchanged but there are some useful clarifications in the final guidance — go here for details.

I thought it might be useful to share reflections from the day. If you’re in a hurry, you can jump to the end and read the summary. If you have a little more time, we’re off to a story in five parts…

First, FDA opened the meeting with a presentation on the details of LPAD along with a brief discussion of the one drug approved to date under LPAD (Arikayce, go here for its 2018 US label). Post-newsletter addendum: Pretomanid was approved in August 2019 under LPAD, bringing the tally to two for LPAD-based drugs (FDA press release, initial US label).

In brief, LPAD uses a 3-part rule of (i) a Serious or Life-Threatening Infection, (ii) a Limited and Defined/Definable Patient Population, and (iii) Unmet Need to point to create the LPAD pathway. The current draft LPAD guidance (link) then explains the utility of LPAD (text begins at line 164, emphasis is mine):

“The LPAD pathway requires FDA to take into account in its determination of safety and effectiveness the severity, rarity, or prevalence of the infection a drug is intended to treat and the lack of alternative treatment in the limited population a drug is intended for (see section 506(h)(2)).
“FDA may approve such drug although not enough data exists to conclude that there is a favorable benefit-risk profile in a broader population.
“As discussed in the Unmet Medical Need guidance, drugs with risks that would be unacceptable for a broad population may be acceptable for patient populations with serious diseases that do not have other treatment options.”

Second, my slides from the day are here and I focused my comments on the idea of Antibiotic R&D v3.0 as a way to see LPAD as a springboard to support development for less common pathogens and infections. Briefly (and please do see the deck):

R&D 1.0 was the period from the dawn of antibiotics to 2005-6 (development was easy, drug effects were obvious),
R&D 2.0 is the period from 2007 to date (single pivotal trials are accepted as sufficient for approval, we update our trial designs, and approval requirements are harmonized globally), and
R&D 3.0 is the period made possible by LPAD in which we extend the zone of approvable compounds to include products for rare pathogens and rare infections.

Third, we had two presentations on specific areas of unmet need for antifungals. Both presentations pointed out the relatively rarity of these infections and the need to work with small datasets to develop new agents.

Fourth (and this is where this note gets really wonkish), all the presentations pointed to some fundamental questions about the utility and purpose of LPAD. To capture the spirit of these interwoven questions, I am going to try a Q&A format. Not all of this was discussed in detail at the public meeting — I am weaving together materials from multiple sources to produce this commentary:

What does LPAD create that didn’t exist before? From one perspective, nothing here is new as FDA has always used benefit-risk as part of its integrated thinking. On the other hand, LPAD does provide FDA with a way to explicitly reinforce the idea of limited use and convey to this the prescribing community. You can see this from the Arikayce label (here): the word “limited” appears 6 times in the first few paragraphs of the left-hand column on page 1, including once as LIMITED (all caps, bold) and again as LIMITED (just all caps). Combined with the requirement for stewardship programs and surveillance by CDC, it is very likely that an LPAD-labeled drug would be used appropriately.

That said, I also think it is noteworthy that the idea of LPAD was to my knowledge first introduced in Jan 2013, the LPAD legislation was signed into law 4 years later (13 Dec 2016), and in the interim FDA effectively implemented most of the elements of LPAD by moving to allow approvals with single pivotal non-inferiority trials and by working to clarify suitable endpoints via various FNIH-led projects (for a summary of this work, see Rex JH et al. Clin Infect Dis 2017, link). Viewed through this lens, it is perhaps unsurprising that LPAD’s impact on approval pathways has been relatively limited — most of what was needed was already up and running, albeit now with explicit statutory blessing from Congress.
Does LPAD make it easier to develop a drug? Are the programs necessarily faster? Are the required data different from the data required for other drugs? Perhaps surprisingly, the answers here are No, No, and No. The standard for approval (21 CFR 314.126) remains “substantial evidence of efficacy based on adequate and well-controlled studies.” Studies of rare pathogens and rare infections remain hard simply because the setting is rare.
Can the developer choose to limit development to a defined small population even though other (larger) populations are readily studied? Inversely, can a developer use LPAD to salvage a failed program seeking broad usage by limiting the scope of approval to a defined small population from the failed program? Again, the general answer to both is No. If there is an obvious way to develop more broadly, then there is strong encouragement to follow that broader path. The core idea here is really to my eye a variant of the reason why antibiotics don’t (usually) qualify for Orphan Drug status. As an example, consider a drug with activity for MBL-producing Enterobacteriaceae. Unless it works only on MBL-producers (that is, it fails on non-MBL-producers), it can be used for both MBL and non-MBL infections. MBL infections may be currently rare (and let’s keep it that way!) but non-MBL are of course very common.

Post-newsletter addendum: The language on this in the FDA’s final 2020 guidance is worth reciting here: “FDA interprets limited population of patients in this provision to mean a group of patients that is limited in a way that is clinically relevant to health care providers. The labeling should define the limited population that the drug is intended to treat so that a health care provider would be able to identify the patients in the clinical setting for whom FDA determined the benefits of the drug outweigh its risks. A limited population may be a defined subset of a broader population of patients for whom the drug could potentially be effective or, in some cases, may be the only population of patients for whom the drug may be effective because of its narrow spectrum of activity.”

In summary, it is critical that the Limited Population have a clear definition that is “clinically relevant to health care providers.” If use cannot readily be contained within the Limited Population, then the idea of approval with higher uncertainty about the benefit-risk in the Limited Population is weakened.
Will (Should) the data in support of an LPAD approval be drawn entirely from the Limited Population for which the drug is approved? Perhaps a surprise here as the answer is No. This subtle but important and VERY confusing point takes us into a discussion of UDR and MDR (Usual Drug Resistance and Multi-Drug Resistance, go here for more on these abbreviations). Although we want new drugs with activity vs. MDR pathogens, we will almost always develop them using a non-inferiority comparison vs. a good comparator in a setting where that comparator has retained activity. For example, consider a study of NEW, a drug for infections due to Enterobacteriaceae. At present, the UDR situation is that most Enterobacteriaceae can be treated with a carbapenem and hence pivotal studies will be of the form NEW vs. meropenem (or imipenem). In such a study there might be a few patients who are incidentally enrolled with a penem-resistant pathogen, but most patients will be infected with a penem-susceptible pathogen. From a public health perspective, it is desirable that it be hard to find penem-resistant infections and hence data on treatment of penem-resistant infections will be limited to some form of small (often non-randomized and open-label) study of NEW.

The core logical leap that comes next is that the correct interpretation of the development program is that NEW works when the pathogen is susceptible to NEW. Stated differently, the MIC of NEW for the infection pathogen contains all the information about NEW’s potential ability to treat infection. A positive result in a non-inferiority comparison with a known effective agent (even if small due to the rarity of the infection) shows that the in vitro MIC predicts clinical response; susceptibility or resistance to other compounds is not relevant. This point is one of the most confusing aspects of the entire problem and I am still looking for better ways to explain it! Good discussions can be found in McDonell AM et al., Clin Infect Dis 2016, Boucher HW et al., J Infect Dis 2017, and Rex JH et al. Nature Comms 2019 (post-newsletter addendum: see this 6 Aug 2019 newsletter for a discussion of the Nat Comms paper, a related paper, and how all this connects to the challenge of non-traditional products). I also gave a talk in 2016 that lays all this out in a slightly different way that is sometimes helpful (link). And for the record, this talk is the very first time the acronym UDR was used in public; its first publication was in the McDonnell 2016 paper cited just above.

Post-newsletter addendum: On this theme, see also this 19 Sep 2020 newsletter entitled “In Praise of Non-Inferiority” along with the related YouTube video on this topic. It is time to learn to love non-inferiority!
I really don’t like the idea of studying patients in the UDR setting … I want to study MDR pathogens in difficult settings! How about an open-label, single-arm, non-comparative series of MDR infections treated with the new agent? This is such a subtle one! In brief, it is not a way out except in rare circumstances (e.g. and post-newsletter addendum, the 2nd LPAD approval of pretomanid uses external control data as context for pretomanid’s activity in XDR TB; go to the top of page 17 of the initial label and then scroll up a tiny bit to see the discussion).

While I am sympathetic to reasons behind the dislike of data from the UDR setting, cold reason shows us that those data are perfectly valid. As noted just above, the MIC really tells almost you everything you need to know about the new agent’s therapeutic potential (again, see also my 2016 talk cited just above). The only gap is that of confirming that PK is as predicted in the relevant patient population(s). A study of critically ill patients (e.g., nosocomial pneumonia) in a UDR setting is the perfect place to gather the needed data in a controlled fashion before resistance becomes widespread. In so doing, we learn about PK in that population, we confirm that the activity is similar to that of a good drug, and we thus know that the new agent is reliable. Safety data may remain limited but presuming there is no cross-resistance, a new drug that matches the performance of meropenem vs. meropenem-susceptible pathogens will continue to perform perfectly well vs. meropenem-resistant pathogens.

For more on the challenges of single-arm data, the best discussion of this problem I’ve seen is Fleming and Ellenberg’s 2016 paper in Clin Trials entitled “Evaluating interventions for Ebola: The need for randomized trials.” Just the title alone should give you pause! In brief, the impact of the new agent must be “sufficiently large to make interpretation of the results of a nonrandomized trial unambiguous.” It’s a great paper — don’t miss the comment about why, in context, randomized trials were not needed to show the value of penicillin! Post-newsletter addendum: Burger’s 2021 paper in Pharm Stat entitled “The use of external controls: To what extent can it currently be recommended?” is also excellent as is (no surprise!) ICH E10 from 2000.
OK, I’ve read that paper, thought about it a bit, and (perhaps grudgingly!) have bought into the value of generating (if possible) at least some randomized UDR-setting data on a new agent. How much data do we need? Now we come back to the point of LPAD. FDA’s requirement for approval is “substantial evidence of efficacy based on adequate and well-controlled studies.” Importantly, alpha = 0.05, 10% margins, specific endpoints, and concurrent randomized controls are not legal requirements. EMA is very explicit about this in their current draft update to their guidance for antibacterial agents (link). Go to line 460 where we are told in a discussion of non-inferiority designs that “The sample size may be driven primarily by feasibility and an estimate of accrual rates over a reasonable time frame (e.g. not exceeding approximately 2 years). There should be a justification for the trade-off proposed between statistical power, nominal significance levels and the non-inferiority margin.” Although we don’t have a corresponding statement from FDA about how they will approach flexibility, we have certainly seen adjustments to margins and there are ongoing discussions about using novel statistical methods (e.g., Bayesian statistics). Hence, I look forward to finding ways to use the principle of LPAD to evolve our thinking and expand the range of approval products. Post-newsletter addendum: Final updates to both EMA and FDA antibacterial guidance documents were released May 2022 and retain the ideas discussed just above. For more, see this 27 May 2022 newsletter.
Who decides how much is enough? Critically, the question of “Who decides?” starts with FDA and EMA but definitely does not end there. Rather, the ultimate arbiter is the clinical community along with the payors (i.e., all of us). The case for a small, focused LPAD-based approval must be solid and compelling — a program uses this pathway because it must, not because it so choses. But, if that’s all a program can do, a good compound should not be held back for lack of a larger dataset. Rather, the very point of LPAD is that rare pathogens are rare, that benefit-risk is different for different populations, and that we can use a clear definition for that limited population to explain this to the entire community.

Fifth (deep inhale and exhale), so what about the elephant in the room? Why was Insmed’s Arikyace (inhaled amikacin) approved under LPAD for treatment of MAC lung disease but Achaogen’s Zemdri (plazomicin) only for cUTI and not also for bacteremia due to CRE? This was not on the agenda for the day, but to my eye boils down to a handful of elements.

The endpoint used for Arikayce was admittedly a surrogate (culture conversion to negative) but the P value (< 0.0001) was very strong whereas the strong endpoint of 28-day all-cause mortality in the Zemdri study had only relatively weak statistical power due the small sample size (a favorable trend, but P > 0.05 in the various analyses from the FDA backgrounder for the 2 May 2018 Ad Comm). Further, the FDA backgrounder makes it clear that the Zemdri program didn’t really have a plan to test a specific statistical hypothesis — so even 28-day all-cause mortality was just descriptive.
All of this was further confounded by the heterogeneity in the patient groups — with only about 20 patients in each arm, it is not surprising that there were imbalances. Unfortunately, these imbalances on the whole tended to predict a better outcome for Zemdri (e.g., somewhat more of the plazomicin patients were blood culture negative at enrollment).
Finally, the limited population for Arikayce is very sharply defined whereas the limited population for Zemdri is little bit fuzzier: people with CRE bacteremia obviously stand out, but what about just bacteremia that might be CRE? Here you can also see elements of the discussion of Orphan Drugs just above in that Zemdri will also work on non-CRE.

So, where does this leave us? My conclusions would be:

LPAD may yet advance the field for us but it’s not a panacea — its impact is limited to a narrow set of problems.
Drugs that can be developed more broadly are not usually appropriate for LPAD. The tools we developed during the Antibiotic R&D 2.0 era are separately in place to permit approval with single trials.
Rather, LPAD’s role as we move into Antibiotic R&D 3.0 is really for very narrowly defined settings that share some of the conceptual features of the Arikyace approval. As specific examples, a sharply defined limited population and a strong clinical signal are foundational. Needing to balance benefit vs. a safety signal is another feature that might support LPAD. In the realm of the more acute bacterial infections, S. aureus endocarditis would be one possibility. Uncommon specific pathogens (e.g., Acinetobacter) might be another. It would be interesting to compile a list … let me know your thoughts.
And, we as a community need to talk about the power of what we learn from standard trials! Going back to Zemdri, how about this tidbit from the label’s discussion of the cUTI dataset: “Composite Cure at the TOC visit in individuals with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the ZEMDRI group and 56.5% (13/23) of patients in the meropenem group.” So, does Zemdri work for bacteremia? Yes, indeed! And will it work for CRE as long as the bug is susceptible to Zemdri? Of course! We need to better explain this. Post-newsletter addendum: On this, I will again encourage you to review this 19 Sep 2020 newsletter entitled “In Praise of Non-Inferiority.” There is even a YouTube video that discusses this issue.

It’s a separate discussion, but I’d be remiss if I didn’t also say that LPAD won’t fix the economics of antibiotics — we really do need good Pull incentives in place. If you are new to this area, please go here for more details on this problem.

Deep stuff indeed! In the spirit of “Tears today vs. tears tomorrow,” it is critical that the entire community engage in discussing these points. I am particularly struck by the difficulty of explaining some of these ideas and will continue to search for better ways to tell the story.

Meditatively yours,

John

Upcoming meetings of interest to the AMR community:

31 Jul 2019 (Philadelphia, PA): Wistar Institute-sponsored “Symposium on Gram-Negative Bacteria Resistance – New Approaches in Pushing Back the Tide.” Go here for details.
20 Aug 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Models for antimicrobial R&D: Computational modelling for population PK and PKPD.” Go here to register.
[Mark your calendar now!] 3-6 Sep 2019 (Boston). Annual ASM-ESCMID Conference on Antibiotic Development. The Bootcamp series will continue on 3 Sep with main meeting on 4-6 Sep. Mark your calendar now and check back here for details.
6 Sep 2019 (Cambridge): CeBIL Annual Symposium 2019: Legal Innovation to Support the Development of Anti-Microbial Drugs. For more details and to register, go here.
6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
2-6 Oct 2019 (Washington, DC): IDSA’s annual IDWeek meeting.
19-27 Oct 2019 (Annecy, France): International Course on Antibiotics and Resistance (ICARe) – A soup-to-nuts intensive residential training program on all things AMR, especially R&D for new antibiotics. See this link for details.
16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): GRC on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
12-13 Mar 2020 (Berlin?): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Final location is TBD, details will appear here, and you should mark your calendar now.
16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details.
18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

Hot meetings x 3! FDA Microbiome AdComm, Diagnostic devices, ASM-ESCMID developer meeting

John Rex — Fri, 26 Aug 2022 12:29:52 +0000

Dear All, I think it’s worth a newsletter to call your attention to several upcoming meetings. In addition to the 30 Aug CDC-FDA webinar on “Drug Development Considerations for the Prevention of Healthcare-Associated Infections” and PACCARB’s 12-13 Sep 2022 pandemic wargaming event, we have these 3 meetings. The first two just now hit my radar and the 3rd is worth a shout-out:

15 Sep 2022 (virtual, 2-4p ET): Duke-Margolis webinar entitled “Advancing Bacterial Diagnostic Development.”
- Mark McClellan’s team at Duke-Margolis consistently assembles instructive webinars and this one will focus on strategies for regulatory clearance of new diagnostics. Don’t miss it!
- Go here for more details and to register.
22 Sep 2022 (virtual, 8.30-5.00p ET): FDA Advisory Committee discussing an application for approval of Rebyota (Fecal Microbiota, Live) with a requested indication to “reduce the recurrence of Clostridioides difficile infection (CDI) in adults following antibiotic treatment for recurrent Clostridioides difficile infection.”
- The P3 data on this product showed superiority over placebo … and the AdComm will doubtless be an important master class for everyone interested in microbiome-based therapies.
- Go here for details.
4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance.
- This series has been one of my favorite meetings since its start … this year it is back and in-person.
- The scientific program looks excellent and the meeting has lots of opportunity for networking.
- I strong encourage attendance! Go here for all the details..

All best wishes, –jr

Job Opportunity with Duke-Margolis! / Phage workshop! / The Martian!

John Rex — Fri, 30 Sep 2022 18:06:10 +0000

Dear All,

I have many times previously shared webinars from the excellent policy team at Duke-Margolis Center for Health Policy. Excitingly if you are in search of that type of role, they are now looking for a Policy Analyst who would be located in either Washington, DC or Durham, NC. Here is the verbatim job summary from the posting:

This position performs a variety of complex activities in research, writing, and analysis of quantitative and/or qualitative data within the scope of research and policy projects focused on antimicrobial resistance (AMR) at Duke University.
The specific topics within antimicrobial resistance vary, but may include policy proposals, innovative payment models, and incentives for antimicrobial product development and availability.
Primary responsibilities include conducting health policy-focused background research; drafting summary documents; performing literature reviews; extensive writing for a range of deliverable types (e.g., policy briefs, white papers, blog posts, peer-reviewed publications); and supporting planning and preparation for Center events, public/private convening, and other project activities through both content development and project/ logistics coordination.

Applicants ideally need a Bachelor’s degree in a field related to the position and two years of experience in policy/research/data analysis or related position. Could this be you? There doesn’t appear to be a deadline but I’d advise you apply soon if you are remotely interested!

—
Separately, please be sure to review the forward agenda. There are two new workshops, including in particular one on phage therapy. I continue to think phage therapy can/will become an important tool but we have yet to see all the pieces come together. The workshop by NIAID and NCATS looks like a very good conversation if you are interested in this area!

—
Finally, if you are looking for a movie recommendation for this weekend, might I suggest The Martian? As you will learn in this ~2min video, antibiotics are important to the entire plot!

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Current funding opportunities (most current list is here)

The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
New funding rounds from CARB-X are expected soon now that funding for the next 10 years has been announced! For the most current update, watch this 30-minute video from the June 2022 kick-off webinar.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent meeting, especially for developers … and if you’ve missed it, the recordings from the 2021 meeting are online. Go here for details on the 2022 meeting.
[NEW] 11 Oct 2022 (virtual, 11a-12.30p ET): REVIVE/GARDP-workshop entitled “Drug discovery strategies: Focusing on synthetic compounds and natural products.” Go here to register.
13-14 Oct 2022 (virtual, 8.30a-5p ET): Workshop entitled “Accelerating the Development & Uptake of Rapid Diagnostics to Address Antibiotic Resistance.” Convened by the National Academies’ Forum on Drug Discovery, Development, and Translation, Forum on Medical and Public Health Preparedness for Disasters and Emergencies, and Forum on Microbial Threats (wow, say that 3 times fast!), this workshop has a broad-ranging agenda focused practical approaches to developing rapid, point-of-care diagnostics. Go here for details and to register.
19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
23 Oct 2022 (Cape Town, South Africa): Symposium entitled “Tackling AMR: How implementation research is vital in a One Health approach” sponsored by the AMR knowledge hub of TGHN (The Global Health Network). Go here for details.
[NEW] 25 Oct 2022 (9a-5p ET): Workshop entitled “Challenges and Solutions to the Development of Bacteriophage Therapy.” Sponsored jointly by NCATS and NIAID, the draft agenda looks to be a very good tour of the challenge and promise of phage. Go here to register.
25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
17-20 Nov 2022 (Kuala Lumpur, Malaysia): The International Congress on Infectious Diseases will take place for the first time as a hybrid event. Go here for details.
27-30 Nov 2022 (Perth, Australia): 32nd International Congress of Antimicrobial Chemotherapy is the biennial congress of the International Society of Antimicrobial Chemotherapy (ISAC). Go here for details.
3-7 Dec 2022 (Banff, Canada): Novel Approaches Against Emerging Antimicrobial Resistance by Keystone Symposia. Go here for details.
8-12 May 2023 (Lisbon, Portugal): 41st Annual Meeting of the European Society for Paediatric Infectious Diseases. Go here for details.

WAAW events: Global voices, FT’s antibiotic dashboard, JPIAMR calls, FAO Action Plan!

John Rex — Fri, 03 Dec 2021 19:01:27 +0000

Dear All,

World Antimicrobial Awareness Week (WAAW) was such a mad scramble! So many events … just no way to attend everything.

Some of the highlights in and around WAAW (not everything was precisely within the WAAW dates, thank goodness!) for me were:

Andrew Jack and the team at FT (Financial Times) have released an antibiotic dashboard that tracks country- and company-level performance on AMR. Andrew and his colleagues are also responsible for an excellent 5-minute video explainer of the Netflix purchase model that the UK is piloting. It is very instructive to note that this financial newspaper has recognized the way that AMR can impact the business world!
FAO (the Food and Agriculture Organization of the UN) has released a 5-year Action Plan (2021-2025) for combating AMR in the food agriculture sector with objectives that include (1) Increasing stakeholder awareness and engagement, (2) Strengthening surveillance and research, (3) Enabling good practices, (4) Promoting responsible use of antimicrobials, and (5) Strengthening governance and allocating resources sustainably.
IDSA released v2.0 of its guidance for treating antimicrobial-resistant Gram-negative infections. As was discussed in this 9 Sep 2020 newsletter, this regularly updated guidance recognizes the need for summaries of what you’d learn if you had a day in library-land with an expert at your elbow. It’s a superb read!
FAO, OIE, and WHO (“the tripartite) released their Global Database for the Tripartite Antimicrobial Resistance (AMR)
Country Self-assessment Survey (TrACSS). Yes, that’s quite a mouthful … but very important! Of the 163 reporting countries to TrACSS this year, 140 countries reported having a national action plan endorsed, implementation and evaluation of those is less as you will see in the database. Progress!
Finally, JPIAMR has posted a heads-up on two calls that will be released early in 2022:
- Disrupting Drug Resistance Using Innovative Design has a focus on improved used of existing drugs
- Diagnostics and Surveillance Networks seeks to assemble networks of experts and stakeholders to facilitate the development, optimization and use of diagnostic and surveillance tools, technologies and systems.

And if that wasn’t enough, then there were the webinars and video chats. I highlight below 4 that I especially enjoyed: Two substantive multi-speaker webinars and two fireside chats that I was able to host with colleagues around the world. I think that these global voices calling for action are very powerful … we are going to get there with the kind of Pull incentives needed to stabilize the antibiotic ecosystem. Enjoy!

The Global AMR Crisis; Does the scale of the action match the scale of the threat? Speakers include Hanan Balkhy (WHO), Ramanan Laxminaryan (CDDEP), Kevin Outterson (Boston University), David Paterson (U Queensland), Yasuhisa Shiozaki (AMR Global Leaders Group), and Lothar Weiler (Robert Koch Institute).

Ensuring Pull Incentives for Priority Antibiotics to Succeed. This superb (as usual) Duke-Margolis seminar includes speakers from Academia (Kevin Outterson, Boston University), national public health agencies (Christine Årdal from Public Health Norway; Nick Crabb from the UK’s NICE, Lynn Filpi from US DHHS), CDC (Arjun Srinivasan), and more. More details (plus other materials from Duke-Margolis) can be found on the event website.

Fireside chat with Ghada Zoubiane, Head of Partnerships and Stakeholder Engagement at the International Centre for Antimicrobial Resistance Solutions (ICARS, based in Denmark) In this wide-ranging conversation, we cover everything from Ghada’s science journey to her views on how science can connect the world. Fun!

This fireside chat takes us to the Land Down Under to meet Trevor Lithgow, Director of the Centre to Impact AMR Strategy at Monash University, Victoria, Australia. Trevor’s journey began with studies of mitochondrial physiology and ultimately took him to working on phage as therapeutics!

With gratitude for this amazing community, –jr

Current funding opportunities (most current list is here):

The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
INCATE (Incubator for Antibacterial Therapies in Europe) is a newly launched early-stage funding vehicle. Details are still coming into focus, but per comments on 25 Aug 2021 at the BIOCOM conference, their goal is to support ~4 companies per year with about $250k/company. Contact details are on their website (https://www.incate.net/).
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

8-9 Dec 2021 (virtual, 9a-noon East Coast US): ASM-ESCMID-sponsored joint conference on antimicrobial drug development. This is the 2021 online version of one of my favorite meetings and I strongly encourage attendance on both days to gain a perspective on how new reimbursement models are going to change the R&D landscape. Online agenda is here, registration link is pending so just mark your calendar for now.
- 8 Dec: “The New Winds Pushing and Pulling Antibacterial Development.” DO NOT MISS THIS ONE! Featuring talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives, this promises to be a key update for the whole community.
- 9 Dec: CARB-X – GARDP Boot Camp: What Makes a Good Project Succeed? Featuring speakers with many years of R&D experience, this session makes a good companion to the 8 Dec talk and will leave you well informed on best ways to guide your search for new antibiotics.
14 Dec 2021 (virtual, 9a-1030a EST): CDC webinar entitled “Hooves, Paws, or Feet: A Multispecies Examination of Antimicrobial Use and Stewardship Practices”. This event is the third installment of the AMR Exchange webinar series. Click here for details.
2-3 Feb 2022 (virtual): 10th Advances Against Aspergillosis and Mucormycocosis. Registration closes on 30 Jan 2022. Go here for details.
2-3 Feb 2022 (virtual): Antimicrobial Chemotherapy Virtual Conference jointly organised by GARDP with the British Society for Antimicrobial Chemotherapy (BSAC), Center for Disease Dynamics, Economics & Policy (CDDEP) and the Indian Council of Medical Research (ICMR). Click here for details.
3-6 Mar 2022 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Details are here.
6-11 Mar 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
7-8 Apr 2022 (Basel and in person, we hope): The 6th edition of the annual AMR conference sponsored by the BEAM Alliance, CARB-X, the Novo REPAIR Impact Fund, the IMI Accelerator, and the European Biotechnology Network. Go here for the hold-the-date page and a way to be kept informed about the meeting.
9-13 May 2022 (Athens and online): 40th Annual Meeting of the European Society for Paediatric Infectious Diseases, Go here for details.
20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.

https://www.youtube.com/watch?v=XZKuEWkJz7w

https://www.youtube.com/watch?v=clSFuAscPqQ

With gratitude for this amazing community, –jr

Current funding opportunities (most current list is here):

The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
INCATE (Incubator for Antibacterial Therapies in Europe) is a newly launched early-stage funding vehicle. Details are still coming into focus, but per comments on 25 Aug 2021 at the BIOCOM conference, their goal is to support ~4 companies per year with about $250k/company. Contact details are on their website (https://www.incate.net/).
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

8-9 Dec 2021 (virtual, 9a-noon East Coast US): ASM-ESCMID-sponsored joint conference on antimicrobial drug development. This is the 2021 online version of one of my favorite meetings and I strongly encourage attendance on both days to gain a perspective on how new reimbursement models are going to change the R&D landscape. Online agenda is here, registration link is pending so just mark your calendar for now.
- 8 Dec: “The New Winds Pushing and Pulling Antibacterial Development.” DO NOT MISS THIS ONE! Featuring talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives, this promises to be a key update for the whole community.
- 9 Dec: CARB-X – GARDP Boot Camp: What Makes a Good Project Succeed? Featuring speakers with many years of R&D experience, this session makes a good companion to the 8 Dec talk and will leave you well informed on best ways to guide your search for new antibiotics.
14 Dec 2021 (virtual, 9a-1030a EST): CDC webinar entitled “Hooves, Paws, or Feet: A Multispecies Examination of Antimicrobial Use and Stewardship Practices”. This event is the third installment of the AMR Exchange webinar series. Click here for details.
2-3 Feb 2022 (virtual): 10th Advances Against Aspergillosis and Mucormycocosis. Registration closes on 30 Jan 2022. Go here for details.
2-3 Feb 2022 (virtual): Antimicrobial Chemotherapy Virtual Conference jointly organised by GARDP with the British Society for Antimicrobial Chemotherapy (BSAC), Center for Disease Dynamics, Economics & Policy (CDDEP) and the Indian Council of Medical Research (ICMR). Click here for details.
3-6 Mar 2022 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Details are here.
6-11 Mar 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
7-8 Apr 2022 (Basel and in person, we hope): The 6th edition of the annual AMR conference sponsored by the BEAM Alliance, CARB-X, the Novo REPAIR Impact Fund, the IMI Accelerator, and the European Biotechnology Network. Go here for the hold-the-date page and a way to be kept informed about the meeting.
9-13 May 2022 (Athens and online): 40th Annual Meeting of the European Society for Paediatric Infectious Diseases, Go here for details.
20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.

Meetings and more: Pandemic wargames! NIAID developer workshop! New stewardship prize!

John Rex — Thu, 12 May 2022 02:27:24 +0000

Dear All, As suggested by the subject line, this newsletter is a bit of a mish-mash of time-critical news about meetings and opportunities! The main thing is to look closely at the funding and meeting summaries below my signature for NEW items. Here are a few highlights:

Do you recall IDSA’s scary 2004 hypothetical scenario in which spread of MDR-Salmonella goes from a “34-year-old expectant mother with vomiting, diarrhea, fever, and chills” on Day 1 to “1,730 deaths and 220,000 illnesses” on Day 6? Well, PACCARB appears set to riff on this by discussing “hypothetical large-scale disease outbreak scenarios based on historic examples and estimates of future AMR outbreaks” on 12-13 Sep 2022. Sounds fascinating and scary! Go here for details.
On 22-23 June 2022, NIAID’s Bacteriology and Mycology Branch (BMB) is hosting a 2-day webinar featuring a very strong faculty (including speakers from FDA) discussing tips and insights for early product discovery. Go here to register.
On 21 June 2022 (yes, the day before NIAID’s event), Vivli is launching an AMR Data Register which aims to provide a platform for the open sharing of AMR surveillance data. Supported with a grant by Wellcome Trust, the AMR Data Register will launch 10a ET via a webinar. This isn’t Vivli’s first rodeo when it comes to online databases — their main database has over 6,400 clinical trials with members from all over the world! This launch sounds like a must if you are interested in surveillance and/or stewardship.
And especially if you are working on stewardship:
- The AMR Industry Alliancehas announced their 2022 Stewardship Prize! The program (application deadline of 31 Aug 2022) offers 10,000 CHF (Swiss Francs, ~$10k) to recognize established, innovative approaches to AMR stewardship in low- and middle-income countries (LMICs).
- WHO have released a pair of training courses on Integrated Stewardship and A Practical Toolkit for Stewardship in LMICs.
And there’s yet more in the updated calendar but I really have to wrap this up … please have a look below my signature!

All best wishes, –jr

Current funding opportunities (most current list is here)

[NEW] The AMR Industry Alliance has announced their 2022 Stewardship Prize! The program offers 10,000 CHF to recognize established, innovative approaches to AMR stewardship in low- and middle-income countries (LMICs). The 2021 prize went to the Infectious Diseases Institute (IDI) in Kampala, Uganda for their best practices in diagnostic stewardship and for their patient awareness campaigns dedicated to decreasing inappropriate use of antibiotics in their specialist HIV clinic in Kampala. Applications for the 2022 prize are due August 31, 2022. Thinking in terms of stewardship, WHO have recently released a pair of courses through the OpenWHO platform:
- Course 1 provides training on the WHO Policy Guidance on Integrated Antimicrobial Stewardship Activities
- Course 2 focuses on the WHO practical toolkit for antimicrobial stewardship programmes in health-care facilities in low- and middle-income countries
- The online training courses can be found on the dedicated channel: https://openwho.org/channels/amr
The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
INCATE (Incubator for Antibacterial Therapies in Europe) is a newly launched early-stage funding vehicle. Details are still coming into focus, but per comments on 25 Aug 2021 at the BIOCOM conference, their goal is to support ~4 companies per year with about $250k/company. Contact details are on their website (https://www.incate.net/).
CARB-X recently announced that their existing resources will be reserved to fund their existing portfolio (more than 80 total awards, and counting, as they include contracting from prior rounds). New rounds from CARB-X will occur only after new funding is obtained in 2021.
It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).

Upcoming meetings of interest to the AMR community (most current list is here):

8 Dec 2021: “The New Winds Pushing and Pulling Antibacterial Development.” This FABULOUS program featured talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives. The video is here — please make time to listen to this program!
The stunning 4 Feb 2022 webinar for the GRAM report (Global Research on Antimicrobial Resistance “1.27 million deaths per year are directly attributable to AMR”) is now available for replay. #AMRSOS!
13 May 2022 (Strasbourg, France): AC21 Workshop: “Pre-clinical development of antimicrobial peptides”, with contributions from the AC21 member universities in Stellenbosch, South Africa, Minneapolis, USA, Freiburg, Germany and Strasbourg, France as well as from other institutions. Participation is free and open to non-member institutions but registration is required. Supported by Academic Consortium 21. Go here for details.
[NEW] 19 May 2022 (virtual): Joint webinar by FAO, OIE, WHO and UNEP entitled “Monitoring national action plans on antimicrobial resistance at country level – best practices”. Go here for details.
[NEW] 8-9 Jun 2022 (virtual, 15.00-18.00 CEST / 9.00-12.00 EDT on both days): “Expert Workshop on Monoclonal Antibodies for AMR Pathogens” sponsored by the Paul-Ehrlich-Institut, on behalf of the COMBINE project. Day 1 focuses on preclinical development and translation (register here); Day 2 focuses on recurring problems and mitigation strategies in the clinical development (register here).
16-18 June 2022 (Perth, Australia): Australasian Society for Infectious Diseases Annual Scientific Meeting is a hybrid event for adult and pediatric infectious disease and clinical microbiology specialists. Go here for details.
[NEW] 21 Jun 2022 (virtual, 10:00-11:00 ET | 15:00-16:00 BST): Launch of the AMR Register. Sponsored by Vivli with funding from many partners, this is the launch of an open-access repository for industry-generated surveillance data. Looks interesting! Go here to register.
[NEW] 22-23 Jun 2022 (virtual, 10a to approx. 2.30p ET on both days): Workshop entitled “Strategies for Early-Stage Programs Developing Novel Antibacterial and Antifungal Drugs.” Sponsored by NIAID’s Bacteriology and Mycology Branch (BMB), this 2-day webinar features a very strong faculty (including speakers from FDA) discussing tips and insights for early product discovery including in-depth discussions of funding opportunities. The timing is US-centered but video replay will be available. Do not miss this! Go here to register.
11-14 July 2022 (Sydney): Australian Society for Microbiology Annual National Meeting is a hybrid event that will feature a range of lectures and symposium sessions, as well as extensive opportunities for networking. Go here for details.
24-27 July 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
28-31 July 2022 (Singapore): 10th International Congress of Asia Pacific Society of Infection Control is a hybrid event for professionals in the Asia Pacific region. Go here for details and to register.
[NEW] 12-13 Sep 2022 (virtual, 9a-5p ET): This meeting of PACCARB is going to “identify key issues and critical policy gaps through a series of facilitated discussions examining a hypothetical large-scale disease outbreak scenario based on historic examples and estimates of future AMR outbreaks.” Sounds like pandemic wargaming (Center for Health Security; pre-COVID 19 May 2020 NPR article) to me! Go here for details.
20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent meeting, especially for developers … and if you’ve missed it, the recordings from the 2021 meeting are online. Go here for details on the 2022 meeting.
19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
15-23 Oct 2022 (in person, residential, Les Pensières, Veyrier-du-Lac, France): The 6^th edition of Patrice Courvalin’s fabulous ICARe residential training course covering all things AMR is on for 2022! This is a soup-to-nuts training in AMR: it is very intense, very detailed, and always gets rave reviews from attendees. Registration is open 21 Mar 2022 to 21 June 2022 and is limited, so book your slot as soon as you can. Go here for details.
19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
[NEW] 17-20 Nov 2022 (Kuala Lumpur, Malaysia): The International Congress on Infectious Diseases will take place for the first time as a hybrid event. Go here for details.
27-30 Nov 2022 (Perth, Australia): 32nd International Congress of Antimicrobial Chemotherapy is the biennial congress of the International Society of Antimicrobial Chemotherapy (ISAC). Go here for details.